Photobiology Unit and Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Br J Dermatol. 2012 Feb;166(2):380-8. doi: 10.1111/j.1365-2133.2011.10661.x. Epub 2012 Jan 9.
There is marked interpatient variation in responses to psoralen-ultraviolet A (PUVA) photochemotherapy. Identification of molecular biomarkers of PUVA sensitivity may facilitate treatment predictability.The glutathione S-transferases (GSTs) influence cutaneous defence against UV radiation-induced oxidative stress and are therefore candidate biomarkers of PUVA sensitivity. Several human GSTs, including GSTM1 and GSTT1, are polymorphic, and null polymorphisms have been associated with increased UVB erythemal sensitivity and skin cancer risk. PUVA also increases skin cancer risk.
To investigate the effect of GST genotype on PUVA sensitivity.
We investigated GST genotype in patients starting PUVA (n=111) and the effects of 8-methoxypsoralen (8-MOP) on antioxidant response element (ARE)-regulated gene expression in mammalian cells.
Lower minimal phototoxic doses (MPD) (P=0·022) and higher serum 8-MOP concentrations (P=0·052) were seen in GSTM1-null allele homozygotes compared with patients with one or two active alleles. In a subset of patients with psoriasis (n=50), the GSTM1 genotype was not associated with PUVA outcomes, although MPD [hazard ratio (HR) 1·37; 95% confidence interval (CI) for HR 1·15-1·64] and GSTT1-null (HR 2·39; 95% CI for HR 1·31-4·35) and GSTP1b (HR 1·96; 95% CI for HR 1·10-3·51) genotypes were associated with clearance of psoriasis in this patient group. Exposure of mammalian cells to 8-MOP induced gene expression via the ARE, a regulatory sequence in promoters of cytoprotective genes including GSTs, suggesting that these genes may be implicated in 8-MOP metabolism.
The polymorphic human GSTs are associated with PUVA sensitivity. Further studies are required to examine the clinical relevance of these preliminary findings.
光化学疗法（PUVA）治疗的个体间反应差异显著。识别 PUVA 敏感性的分子生物标志物可能有助于提高治疗预测性。谷胱甘肽 S-转移酶（GSTs）影响皮肤对 UV 辐射诱导的氧化应激的防御，因此是 PUVA 敏感性的候选生物标志物。几种人类 GSTs，包括 GSTM1 和 GSTT1，存在多态性，且无效多态性与增加的 UVB 红斑敏感性和皮肤癌风险相关。PUVA 也会增加皮肤癌风险。
研究 GST 基因型对 PUVA 敏感性的影响。
我们调查了开始接受 PUVA 治疗的患者（n=111）的 GST 基因型，以及 8-甲氧基补骨脂素（8-MOP）对哺乳动物细胞抗氧化反应元件（ARE）调节基因表达的影响。
与具有一个或两个活性等位基因的患者相比，GSTM1 无效等位基因纯合子的最小光毒性剂量（MPD）（P=0·022）更低，血清 8-MOP 浓度更高（P=0·052）。在一组银屑病患者（n=50）中，GSTM1 基因型与 PUVA 结局无关，尽管 MPD [危险比（HR）1·37；95%置信区间（CI）的 HR 为 1·15-1·64]、GSTT1 无效（HR 2·39；95% CI 的 HR 为 1·31-4·35）和 GSTP1b（HR 1·96；95% CI 的 HR 为 1·10-3·51）基因型与该患者群体中银屑病的清除相关。8-MOP 使哺乳动物细胞暴露于 ARE 诱导基因表达，ARE 是包括 GSTs 在内的细胞保护基因启动子中的调控序列，这表明这些基因可能参与 8-MOP 代谢。
人类 GSTs 的多态性与 PUVA 敏感性相关。需要进一步研究以检验这些初步发现的临床意义。
